Quinoline carboxylic acid derivatives

ABSTRACT

The present invention relates to a quinolone carboxylic acid derivative represented by the following the formula (I), ##STR1## wherein R 1  is a lower alkyl group, R 2  is a hydrogen atom or a lower alkyl group, R 3  is a hydrogen atom or a halogen atom, R 4  and R 5  together form a five- or six-membered ring which may contain hetero atoms or may have substituents, provided that a compound wherein R 1  is a methyl group, R 2  and R 3  are hydrogen atom and ##STR2## is a piperazinyl group is excluded; or a salt thereof; to an antimicrobial agent comprising the same as an effective component; and to an intermediate for producing same.

FIELD OF THE INVENTION

The present invention relates to a novel quinolone carboxylic acidderivative and a salt thereof which have excellent antimicrobialactivity, to an antimicrobial agent comprising the same as an effectivecomponent, and to an intermediate for producing the same.

DESCRIPTION OF THE BACKGROUND

Synthetic antimicrobial agents such as nalidixic acid, piromidic acid,and the like are known as drugs for curing infectious diseases caused byGram negative microorganisms. They exhibit, however, only deficienteffects on intractable diseases such as pseudomoniasis and the like. Onthe other hand, antimicrobial agents with a stronger antimicrobialactivity, such as norfloxacin, ofloxacin, and the like, have beendeveloped and clinically used.

In order for an antimicrobial agent to effectively exhibit its action,the agent must have a strong antimicrobial activity and must beefficiently utilized. The above-mentioned conventional syntheticantimicrobial agents had a defect in that they are insufficientlyabsorbed, thus achieving only low utilization by living bodies.

In view of such a situation, the present inventors have synthesized anumber of quinolone carboxylic acid derivatives and studied theirantimicrobial activity and absorption efficiency by living bodies, andfound that quinolone carboxylic acid derivatives of the followingformula (I) and their salts exhibited excellent antimicrobial activitiesand superior absorptivity. Such a finding has led to the completion ofthe present invention.

DISCLOSURE OF THE INVENTION

An object of the present invention is to provide a quinolone carboxylicacid derivative having the following formula (I), ##STR3## wherein R₁ isa lower alkyl group, R₂ is a hydrogen atom or a lower alkyl group, R₃ isa hydrogen atom or a halogen R₄ and R₅ together form a five- orsix-membered ring which may contain hetero atoms or may havesubstituents, provided that a compound wherein R₁ is methyl group R₂ andR₃ are hydrogen atoms and ##STR4## is a piperazinyl group is excluded;or a salt thereof; to an antimicrobial agent comprising the same as aneffective component; and to an intermediate for producing the same.

In the present invention, groups represented by ##STR5## includepiperazinyl, pyrrolidinyl, morpholino, and lower alkyl groups, hydroxygroups, amino groups, amino-lower-alkyl groups, are given as examples ofthe substituents.

In the present invention, an alkyl group is normally means a linear orbranched alkyl group having 1-6 carbon atoms, specifically, methyl,ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, n-pentyl, n-hexyl,or the like. Examples given of halogen atoms are chlorine, bromine,iodine, fluorine.

The salts of the compounds of formula (I) of the present invention arenot specifically limited so long as they are physiologically acceptablesalts, and include salts of alkali metal, alkaline earth metal,inorganic acid, organic acid, and the like. Specific examples which canbe given as salts of alkali metal are lithium salt, sodium salt,potassium salt, and the like; as salts of inorganic acids arehydrochloride, sulfate, nitrate, hydrobromide, phosphate, and the like;and as salts of organic acid are acetate, fumarate, maleate, lactate,citrate, tartrate malate, oxalate, methanesulfonate, benzenesulfonate,and the like.

The compounds of the present invention may have an asymmetric carbonatom depending the type of the group ##STR6##

The present invention include both the optical isomers and mixturesthereof.

The compound of formula (I) of the present invention can be prepared byone of the following processes. ##STR7## wherein R₂₋₁ is a lower alkylgroup, X is a halogen atom, R₁, R₃, R₄, and R₅, are the same as thosepreviously defined.

According to the above process, compound (II) is halogenized intocompound (III), which is reacted with an amine (IV) to produce compound(V). Compound (V) is then dehydrohalogenized and hydrolyzed to givecompound (I) or its salt of this invention.

The raw material, compound (II), can be prepared by the method describedin DE 3,522,406.

In order to prepare compound (III) from compound (II), 1 mol of compound(II) is reacted with 1-5 mols of a halogenizing agent in a solvent atroom temperature or under refluxing temperature for 1-20 hours. As ahalogenizing agent, thionyl chloride, thionyl bromide, phosphorusoxychloride, phosphorus trichloride, phosphorus tribromide, phosphoruspentachloride, or the like may be used. Methylene chloride, chloroform,carbon tetrachloride, 1,2-dichloroethane, trichloroethane, or the likemay be used as a solvent. After the reaction, the reaction product isconcentrated, and the residue is purified by silica gel columnchromatography to obtain compound (III).

In order to produce compound (V) from compound (III), 1 mol of compound(III) is reacted with 1-5 mols of compound (IV) in a solvent, such asdimethylsulfoxide, acetonitrile, or the like, at room temperature to100° C. for 1-15 hours. After the reaction, the reaction mixture ispoured into cold water, neutralized with an acid, and extracted with asolvent such as chloroform or the like. After evaporation of the solventor after concentrating the reaction product, the residue is washed withwater to obtain a crude product, which is purified by silica gel columnchromatography or by the recrystallization to obtain compound (V).

For preparing compound (I-1) from compound (V), 1 mol of compound (V) isreacted with 2-4 moles of an alkali in a solvent such as ethanol or thelike while heating for 5-60 hours, followed by an addition of water anda further reaction with heating for 1-20 hours. Sodium hydroxide orpotassium hydroxide is preferably used as an alkali. After the reaction,the reaction product is poured into cold water, neutralized with anacid, and extracted with a solvent such as chloroform or the like. Afterevaporation of the solvent, the residue is recrystallized from asuitable solvent to obtain pure compound (I-1). ##STR8## wherein P is aprotective group, L is a leaving group, and R₁, R₂₋₁, R₄, and R₅, and Xhave the same meaning as previously defined.

According to the above process, compound (VI) is reacted with compound(VII), which is halogenized to produce compound (IX). Compound (XI) isthen reacted with an amine (IV) to obtain compound (I-2). Compound (I-2)is further hydrolyzed into compound (I-3).

The raw material, compound (VI), is a known compound. It can beprepared, for example, by the method described in J. Med. Chem. 23, 1358(1980). In order to prepare compound (VIII) from compound (VI), 1 mol ofcompound (VI) is reacted with 2-4 mols of alkaline carbonate in asolvent such as dimethylformamide or the like at room temperature orunder refluxing temperature for 1-20 hours. After the reaction, thereaction product is concentrated, acidified with acetic acid or thelike, warmed at 40°-80° C. for 1-5 hours, and concentrated. The residueis extracted with a solvent such as chloroform or the like and purifiedby silica gel column chromatography, and, if necessary, may berecrystallized, to obtain compound (VIII).

The reaction for the production of compound (IX) from compound (VIII)can be carried out in the same manner as the reaction for obtainingcompound (III) from compound (II) in Process 1.

For producing compound (I-2) from compound (IX), 1 mole of compound (IX)is reacted with 1-5 mols of compound (IV) in a solvent, such asdimethylsulfoxide, acetonitrile, or the like, at room temperature to100° C. for 1-60 hours. After the reaction, the reaction mixture ispoured into cold water and extracted with a solvent such as chloroformor the like. The chloroform layer is reverse-extracted with an acid, thewater layer is alkalinized and again extracted with chloroform or thelike. After removal of solvent the residue is purified by silica gelcolumn chromatography to obtain compound (1-2).

In the reaction for preparing compound (I-3) from compound (I-2),compound (I-2) is heated in the presence of an alkali such as sodiumhydroxide, potassium hydroxide, or the like in an aqueous alcohol for1-5 hours. After the reaction, the reaction product is neutralized withan acid, concentrated and extracted with a solvent such as alcohol orthe like. After evaporation of the solvent, the residue is purified bythe recrystallization or the like to obtain compound (I-3).

If necessary, compound (I) thus obtained is converted into a salt, suchas a salt of alkali metal, alkaline earth metal, inorganic acid, organicacid, or the like, according to a conventional method.

When the compound thus produced is a racemate, the optical isomer can beobtained, if desired, for example, by reacting it with an opticallyactive acid to form a diastereomer and by separating the optical isomerby recrystallization, chromatography, or the like means. If the opticalisomer cannot be separated, the target optical isomer with a desiredstereoscopic structure can be prepared by using an optically active rawmaterial.

When compound (I) of this invention thus prepared is used as anantimicrobial agent, it is preferably orally administered at a dose of200 to 800 mg per day or parenterally at a dose of 5 to 40 mg per day,depending on the weight, the age, the sex, the physical conditions, orthe symptom of the patient or the manner of administration.

Compound (I) can be formed into various antimicrobial preparations, suchas tablets, granules, powders, capsules, suspensions, injections,suppositories, or the like, according to conventional methods. Whensolid preparations are produced, compound (I) is mixed with excipients,and as required, with binders, disintegrators, lubricants, coloringagents, sweetening agents, flavoring agents, fillers, coating agents,sugar-coating agents, and the like, and formed into preparations such astablets, granules, powders, capsules, suppositories, or the likeaccording to known methods. When compound (I) is made into a preparationfor injection, it is by dissolved, suspended, or emulsified into anaqueous medium such as distilled water, or made into powder which isdissolvable when it is injected. Intravenous, intraarterial,intraportal, intraperitoneal, subcutaneous, or intramuscular injectionare applicable.

EXAMPLES

The present invention is hereinafter described in more detail by way ofexamples and test examples, which are not intended to be limitingthereof.

Reference Example 1 Ethyl1-(1-chloroprop-2-yl)-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate

0.988 gm (3.0 mmol) of ethyl6,7,8-trifluoro-1,4-dihydro-1-(1-hydroxyprop-2-yl)-4-oxoquinoline-3-carboxylatewas dissolved into 50 ml of chloroform. To this was added 0.714 gm (6.0mmol) of thionyl chloride and the mixture was reacted with heating underrefluxing for 10 hours. The reaction mixture was concentrated underreduced pressure and the residue was purified by silica gel columnchromatography (chloroform:methanol=100:1) to obtain 1.001 gm ofcolorless, needlelike crystals of ethyl1-(1-chloroprop-2-yl)-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate.

mp 190°-191° C.

IR (KBr): 1730, 1618 cm⁻¹.

¹ H-NMR (CDCl₃) δ ppm: 1.40(3H, t, J=7.2Hz), 1.77(3H, d, d, J=6.5,1.8Hz), 3.89(2H, d, d, J=5.5, 1.8Hz), 4.31(2H, q, J=7.2Hz), 5.2-5.7(1H,m), 7.9-8.3(1H, m), 8.58(1H, s).

Example 1 Ethyl7-(3-amino-1-pyrrolidinyl)-1-(1-chloroprop-2-yl)-6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate

174 mg (0.5 mmol) of ethyl1-(1-chloroprop-2-yl)-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylatewas dissolved into 20 ml of acetonitrile. To this was added 215 mg (2.5mmol) of 3-aminopyrrolidine and the mixture was reacted with heatingunder refluxing for 7 hours. The reaction mixture was concentrated underreduced pressure and the residue was purified by silica gel columnchromatography (chloroform:methanol=100:1-20:1) to obtain 172 mg oflight yellow crystals of ethyl7-(3-amino-1-pyrrolidinyl)-1-(1-chloroprop-2-yl)-6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate(Compound No. 1).

Compound Nos. 2-18 shown in Table 1 were prepared in the same manner asin this example.

                                      TABLE 1                                     __________________________________________________________________________     ##STR9##                                                                      No.poundCom-                                                                      R.sub.1                                                                          R.sub.2-1                                                                        ##STR10##  R.sub.3                                                                         X                                                                               mp (°C.)Property                                                              or KBr)(NaCl-filmIR cm.sup.-1                                                       .sup.1 H-NMR ppm                       __________________________________________________________________________                                          (CDCl.sub.3)                             1  CH.sub.3                                                                         C.sub.2 H.sub.5                                                                   ##STR11## F Cl                                                                              light yellow crystals 106-108                                                        3420, 3340, 1720, 1680                                                              1.41(3H, t, J=7.2Hz), 1.70(2H, s),                                            1.73(2H, d, d,  J=6.6, 1.5Hz),                                                1.8-2.3(2H, m), 3.2-4.1(7H, m),                                               4.39(2H, q, J=7.1Hz), 5.0-5.5(1H,                                             m), 7.89(1H, d, d, J=14.1, 2.0Hz),                                            8.47(1H, s)                              2  CH.sub.3                                                                         C.sub.2 H.sub.5                                                                   ##STR12## F Cl                                                                              light yellow oil                                                                     3320, 1730, 1692                                                                    1.42(3H, t, J=7.2Hz), 1.77(3H, d,                                             d, J=7.0, 1.8Hz), 2.20(1H, s),                                                2.8-3.5(8H, m), 3.90(2H, d, d,                                                J=5.5, 3.0Hz), 4.41(2H, q,                                                    J=7.2Hz), 5.0-5.7(1H, m), 7.98(1H,                                            d, d, J=12.5, 1.8Hz), 8.58(1H, s)        3  CH.sub.3                                                                         C.sub.2 H.sub.5                                                                   ##STR13## F Cl                                                                              light brown needlelike crystals 117-120                                              1728, 1692                                                                          1.39(3H, t, J=7.2Hz), 1.74(3H, d,                                             J=6.5Hz), 2.83(3H, s), 2.4-2.8(4H,                                            m), 3.2-3.6(4H, m), 3.87(2H, d, J=                                            5.5Hz), 4.40(2H, q, J=7.2Hz),                                                 5.1-5.8(1H, m), 7.97 (1H, d, d,                                               J=11.5, 1.8Hz), 8.53(1H, s)              4  CH.sub.3                                                                         C.sub.2 H.sub.5                                                                   ##STR14## F Cl                                                                              light yellow- brown crystals 121-124                                                 3490, 1727 1690                                                                     1.06(3H, d, J=5.7Hz), 1.42(3H, t,                                             J=7.1Hz), 1.74(3H, d, d, J=1.8,                                               6.8Hz), 2.05(1H, s), 2.6-3.4(7H,                                              m), 3.8-4.0(2H, m), 4.40(2H, q,                                               J=7.2Hz), 5.2-5.4(1H, m) 7.97(1H,                                             d, d, J=12.1, 1.9Hz), 8.52(1H, s)        5  CH.sub.3                                                                         C.sub.2 H.sub.5                                                                   ##STR15## F Cl                                                                              light orange crystals 147-149                                                        1720, 1690                                                                          1.41(3H, t, J=7.2Hz), 1.73(3H, d,                                             d, J=6.7, 1.7Hz), 1.8-2.0(4H, m),                                             3.5-3.8(4H, m), 3.84(2H, d, d,                                                J=5.8, 1.9Hz), 4.39(2H, q,                                                    J=7.2Hz), 5.1-5.6(1H, m), 7.88(1H,                                            d, d, J=14.2, 2.0Hz), 8.47(1H, s)        6  CH.sub.3                                                                         C.sub.2 H.sub.5                                                                   ##STR16## F Cl                                                                              light yellow crystals 177-180                                                        3410, 1722 1612                                                                     1.40(3H, t, J=7.0Hz), 1.72(3H,                                                br.d, J=6.9Hz), 1.8-2.2(2H, m),                                               2.95(1H, br.s), 3.4-4.2(6H, m),                                               4.38 (2H, q, J= 7.0Hz), 4.4-4.6(1H,                                           m), 5.1-5.5(1H, m), 7.75(1H, br.d,                                            J=13.8Hz), 8.45, 8.47(1H, eachs)         7  C.sub.2 H.sub.5                                                                  C.sub.2 H.sub.5                                                                   ##STR17## F Cl                                                                              light brown oil                                                                      3310, 1724, 1690                                                                    1.02(3H, t, J=7.3Hz), 1.42(3H, t,                                             7.0Hz), 1.9-2.3(3H, m, 1H                                                     disappeared by D.sub.2 O),                                                    2.8-3.1(4H, m), 3.1-3.4 (4H, m),                                              3.8-4.0(2H, d-like), 4.39(2H, q,                                              J=7.0Hz), 4.9-5.11(1H, m), 7.98(1H,                                           d, d, J=2.0, 12.1Hz), 8.49(1H, s)        8  C.sub.2 H.sub.5                                                                  C.sub.2 H.sub.5                                                                   ##STR18## F Cl                                                                              light brown oil                                                                      2945, 1724 1689                                                                     1.02(3H, t, J=7.3Hz), 1.42(3H, t,                                             J=7.0Hz), 1.9-2.2 (2H, m), 2.37(3H,                                           s), 2.4-2.7(4H, m), 3.2-3.5 (4H,                                              m), 3.8-4.0(2H, d, d-like),                                                   4.40(2H, q, J=7.0Hz), 4.9-5.4(1H,                                             m), 7.98(1H, d, d, J=11.9, 1.8Hz),                                            8.48(1H, s)                              9  C.sub.2 H.sub.5                                                                  C.sub.2 H.sub.5                                                                   ##STR19## F Cl                                                                              light yellow needlelike crystals 115-119                                             3350, 1715 1612                                                                     1.00(3H, t, J=7.2Hz), 1.41(3H, t,                                             J=7.0Hz), 1.64(2H, br.s.                                                      disappeared by D.sub.2 O),                                                    1.6-2.3(4H, m), 3.2-4.0 (7H, m),                                              4.38(2H, q, J=7.2Hz), 4.8-5.2(1H,                                             m), 7.89(1H, d, d, J=14.1, 1.8Hz),                                            8.44(1H, s)                             10  CH.sub.3                                                                         C.sub.2 H.sub.5                                                                   ##STR20## H Cl                                                                              light yellow- needlelike crystals 135-140                                            3430, 1718 1632                                                                     1.41(3H, t, J=7.1Hz), 1.67(2H,                                                br.s), 1.75(3H, d, J=7.0Hz),                                                  1.6-2.4(2H, m), 3.2-4.0(7H, m),                                               4.39(2H, q, J=7.1Hz), 4.6-5.1(1H,                                             m), 6.35(1H, d, J=6.8Hz), 8.00(1H,                                            d, J=14.4Hz), 8.44(1H, s)               11  CH.sub.3                                                                         C.sub.2 H.sub.5                                                                   ##STR21## H Cl                                                                              light brown needlelike crystals 156-159                                              2950, 1720 1612                                                                     1.41(3H, t, J=7.3Hz), 1.77(3H, d,                                             J=6.6Hz), 2.38(3H,  s), 2.4-2.7(4H,                                           m), 3.1-3.4(4H, m), 3.84(2H, d,                                               J=5.7Hz), 4.39(2H, q, J=7.3Hz),                                               4.7-5.1(1H, m), 6.82(1H, d,                                                   J=7.0Hz), 8.08(1H, d, J=13.2Hz),                                              8.50(1H, s)                             12  CH.sub.3                                                                         C.sub.2 H.sub.5                                                                   ##STR22## H Cl                                                                              light brown amorphous 57-64                                                          3425, 1720 1620                                                                     1.16(3H, d, J=6.6Hz), 1.41(3H, t,                                             J=7.0Hz), 1.77(3H, d, J=6.6Hz),                                               2.19(1H, s, disappeared by D.sub.2                                            O), 2.3-3.2(5H, m), 3.3-3.6(2H,                                               d-like), 3.85(2H, d, J=5.7Hz),                                                4.39(2H, q, J=7.0Hz), 4.7-5.1(1H,                                             m), 6.82(1H, d, J=6.6Hz), 8.08(1H,                                            d, J=13.2Hz), 8.50(1H, s)               13  CH.sub.3                                                                         C.sub.2 H.sub.5                                                                   ##STR23## H Cl                                                                              light brown crystals 196-199                                                         3425, 1712, 1626                                                                    1.41(3H, t, J=7.0Hz), 1.76(3H, d,                                             J=6.2Hz), 1.9-2.2 (4H, m),                                                    3.4-3.7(4H, m), 3.83(2H, d,                                                   J=5.3Hz), 4.38(2H, q, J=7.0Hz),                                               4.6-5.1(1H, m), 6.35(1H, d,                                                   J=7.5Hz), 7.99(1H, d, J=14.5Hz),                                              8.43(1H, s)                             14  C.sub. 2 H.sub.5                                                                 C.sub.2 H.sub.5                                                                   ##STR24## H Cl                                                                              light brown crystals 147-155 (dec)                                                   3425, 1715 1628                                                                     0.98(3H, t, J=7.3Hz), 1.39(3H, t,                                             J=7.0Hz), 1.6-2.5 (6H, m, 2H                                                  disappeared by D.sub.2 O),                                                    3.2-3.8(5H, m), 3.86(2H, d,                                                   J=5.7Hz), 4.37(2H, q, J=7.0Hz),                                               4.5-4.8 (1H), m), 6.37(1H, d,                                                 J=6.6Hz), 7.94(1H, d, J=14.5Hz),                                              8.37(1H, s)                             15  C.sub.2 H.sub.5                                                                  C.sub.2 H.sub.5                                                                   ##STR25## H Cl                                                                              light brown amorphous 68-73                                                          3450, 1720 1620                                                                     0.99(3H, t, J=7.3Hz), 1.42(3H, t,                                             J=7.0Hz), 1.9-2.25 (2H, m),                                                   2.39(3H, s), 2.5-2.8(4H, m),                                                  3.2-3.4(4H, m), 3.89(2H, d,                                                   J=6.6Hz), 4.40(2H, q, J=7.0Hz),                                               4.6-4.8(1H, m), 6.85(1H, d,                                                   J=6.6Hz), 8.10 (1H, d, J=13.2Hz),                                             8.45(1H, s)                             16  C.sub.2 H.sub.5                                                                  C.sub.2 H.sub.5                                                                   ##STR26## H Cl                                                                              light brown amorphous 88-94                                                          3420, 1717 1615                                                                     1.00(3H, t, J=7.3Hz), 1.42(3H, t,                                             J=7.1Hz), 1.8-2.3 (2H, m), 2.40(1H,                                           br.s), 3.0-3.4(8H, m), 3.89(2H, d,                                            J=6.2Hz), 4.40(2H, q, J=7.1Hz),                                               4.5-4.9(1H, m), 6.86(1H, d,                                                   J=7.0Hz), 8.10(1H, d, J=13.2Hz),                                              8.45(1H, s)                             17  C.sub.2 H.sub.5                                                                  C.sub.2 H.sub.5                                                                   ##STR27## H Cl                                                                              brown amorphous 64-69                                                                3430, 1720 1615                                                                     0.99(3H, t, J=7.3Hz), 1.17(3H, d,                                             J=6.6Hz), 1.42(3H, t, J=7.0Hz),                                               1.9-2.3(3H, m), 2.3-2.7(1H, m),                                               2.7-3.3 (4H, m), 3.3-3.8(2H, m),                                              3.89(2H, d, J=5.7Hz), 4.40(2H, q,                                             J=7.0Hz), 4.5-4.9(1H, m), 6.84(1H,                                            d, J=6.6Hz), 8.10(1H, d, J=13.6Hz),                                           8.45(1H, s)                             18  C.sub.2 H.sub.5                                                                  C.sub.2 H.sub.5                                                                   ##STR28## H Cl                                                                              brown crystals 165-170                                                               3500, 1720 1610                                                                     0.98(3H, t, J=7.3Hz), 1.42(3H, t.                                             J=7.2Hz), 1.8-2.6  (6H, m),                                                   3.3-3.7(4H, m), 3.86(2H, d,                                                   J=5.7Hz), 4.39(2H, q, J=7.2Hz),                                               4.5-4.8(1H, m), 6.39(1H, d,                                                   J=7.0Hz), 8.03(1H, d, J=14.5Hz),                                              8.38(1H, s)                             __________________________________________________________________________

Example 27-(3-Amino-1-pyrrolidinyl)-6,8-difluoro-1,4-dihydro-4-oxo-1-(prop-1-en-2-yl)-quinoline-3-carboxylicacid

159 mg (0.38 mmol) of ethyl7-(3-amino-1-pyrrolidinyl)-1-(1-chloroprop-2-yl)-6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate(Compound No.1) prepared in Example 1 was dissolved into 20 ml ofethanol. To this was added 65 mg (1.15 mmol) of pulverized potassiumhydroxide and the mixture was heated under refluxing for 14 hours. 3 mlof water was added and the mixture was heated under refluxing for afurther 3 hours. After cooling, the reaction mixture was concentratedunder reduced pressure, the residue was washed with water, and dried toobtain a crude product. The crude product was purified by silica gelcolumn chromatography (chloroform:methanol=5:1) to obtain 52 mg of lightyellow crystals of7-(3-amino-1-pyrrolidinyl)-6,8-difluoro-1,4-dihydro-4-oxo-1-(prop-1-en-2-yl)-quinoline-3-carboxylicacid (Compound No. 19).

Compound Nos. 20-36 shown in Table 2 were prepared in the same manner asin this example.

                                      TABLE 2                                     __________________________________________________________________________     ##STR29##                                                                     No.poundCom-                                                                       R.sub.1                                                                          R.sub.2                                                                         ##STR30##  R.sub.3                                                                         mp (°C.)Property                                                            (KBr)IR cm.sup.-1                                                                    (CDCl.sub.3).sup.1 H-NMR                  __________________________________________________________________________                                       ppm                                        19   CH.sub.3                                                                         H                                                                                ##STR31## F light yellow crystals 174-178 (dec)                                                3400, 1720, 1610                                                                     1.5-2.2(2H, m), 2.20(3H, s),                                                  3.0-4.0(7H, m), 5.40 (2H, br),                                                7.60(1H, br.d), 8.41(1H, s)                20   CH.sub.3                                                                         H                                                                                ##STR32## F light yellow- brown crystals 188-192 (dec)                                         3420, 1720, 1620                                                                     2.23(3H, s), 2.9-3.2(4H, s),                                                  3.2-3.5(4H, m), 5.29 (1H, s), 5.40(1H,                                        s), 7.94(1H, d, d, J=11.9, 2.0Hz),                                            8.55(1H, s)                                21   CH.sub.3                                                                         H                                                                                ##STR33## F light brown prismlike crystals 225-227 (dec)                                       1722, 1618                                                                           2.25(3H, s), 2.40(3H, s), 2.5-2.8(4H,                                         m), 3.3- 3.6(4H, m), 5.32(1H, s),                                             5.39(1H, s), 7.88(1H, d, d, J=12.0,                                           1.8Hz), 8.52(1H, s)                        22   CH.sub.3                                                                         H                                                                                ##STR34## F light yellow crystals 181-184 (dec)                                                3425, 1720, 1612                                                                     1.11(3H, d, J=5.5Hz), 2.22(3H, s),                                            2.7-3.5(8H, m) 5.28(1H, s), 5.37(1H,                                          s), 5.5-6.7(1H, br), 7.91 (1H, d, d,                                          J=11.9, 2.0Hz), 8.52(1H, s)                23   CH.sub.3                                                                         H                                                                                ##STR35## F light yellow needle- like crystals 251-253                                         1722, 1620                                                                           1.5-2.1(5H, m), 2.20(3H, s),                                                  3.6-4.0(4H, m), 5.27 (1H, s), 5.32(1H,                                        s), 7.81(1H, d, d, J=13.9, 1.9Hz),                                            8.48(1H, s)                                24   CH.sub.3                                                                         H                                                                                ##STR36## F light yellow prismlike crystals 251-252 (dec)                                      3450, 1710, 1622                                                                     1.6-2.2(3H, m), 2.20(3H, s),                                                  3.4-4.2(4H, m), 4.4- 4.7(1H, m),                                              5.27(1H, s), 5.32(1H, s), 7.80(1H, d,                                         d, J=13.9, 2.0Hz), 8.45(1H, s)             25   C.sub.2 H.sub.5                                                                  H                                                                                ##STR37## F white powderly crystal 229-234 (dec)                                               3380, 1720, 1700                                                                     1.10(3H, t, J=7.4Hz), 2.3-2.7(2H,                                             q-like), 2.7- 3.4(6H, m), 3.4-3.7(4H,                                         m), 5.46(1H, s), 5.52(1H s), 7.88(1H,                                         d, d, J=11.9, 2.0Hz), 8.48(1H, s)          26   C.sub.2 H.sub.5                                                                  H                                                                                ##STR38## F light yellow powdery crystal 232-240 (dec)                                         3425, 1718, 1606                                                                     1.10(3H, t, J=7.4Hz), 2.3-2.7(2H,                                             q-like, 2.78 (3H, s), 2.9-3.4(5H, m),                                         3.5-3.8(4H, m), 5.46(1H, s), 5.52(1H,                                         s), 7.89(1H, d, d, J=11.9, 2.0Hz),                                            8.48 (1H, s)                               27   C.sub.2 H.sub.5                                                                  H                                                                                ##STR39## F light yellow powder- lye crystals 217-222 (dec)                                    3430, 1700, 1620                                                                     1.08(3H, t, J=7.4Hz), 1.8-2.3(2H, m),                                         2.3-2.6 (2H, m), 2.8-4.6(7H, m),                                              5.42(1H, s), 5.49(1H, s), 7.77(1H, d,                                         d, J=14.0, 1.9Hz), 8.40(1H, s)             28   CH.sub.3                                                                         H                                                                                ##STR40## H light brown powderly crystal 221-225 (dec)                                         3420, 1690, 1632                                                                     1.6-2.4(2H, m), 2.24(3H, s),                                                  3.0-4.1(5H, m) 5.54(1H, s), 5.74(1H,                                          s), 6.47(1H, d, J=7.5Hz) 7.85(1H, d,                                          J=14.1Hz), 8.57(3H, s, 2H disappeared                                         by D.sub.2 O)                              29   CH.sub.3                                                                         H                                                                                ##STR41## H light yellow- brown powderly crystal 240-244                                       3425, 1722, 1624                                                                     2.25(6H, s), 2.4-2.6(4H, m),                                                  2.6-3.6(5H, m) 5.55(1H, s), 5.73(1H,                                          s), 6.90(1H, d, J=7.4Hz), 7.87(1H, d,                                         J=13.5Hz), 8.61(1H, s)                     30   CH.sub.3                                                                         H                                                                                ##STR42## H light brown powderly crystal 212-217 (dec)                                         3450, 1720, 1622                                                                     1.30(3H, d, J=5.9Hz), 2.25(3H, s),                                            2.8-3.8(7H, m), 4.0-5.4(1H, br),                                              5.56(1H, s), 5.75(1H, s), 6.95 (1H, d,                                        J=7.2Hz), 7.91(1H, d, J=13.3Hz),                                              8.63(1H, s)                                31   CH.sub.3                                                                         H                                                                                ##STR43## H light brown powderly crystal 276-281 (dec)                                         2960, 1720, 1624                                                                     1.8-2.1(4H, m), 2.22(3H, s),                                                  3.4-3.6(4H, m), 5.50 (1H, s), 5.69(1H,                                        s), 6.47(1H, d, J=7.9Hz), 7.81(1H, d,                                         J=14.4Hz), 8.51(1H, s)                     32   C.sub.2 H.sub.5                                                                  H                                                                                ##STR44## H light brown powderly crystal 178-184 (dec)                                         3425, 1720, 1710                                                                     1.09(3H, t, J=7.3Hz), 2.0-2.3(2H, m),                                         2.4-2.7 (2H, m), 2.8-4.0(9H, m),                                              5.60(1H, s), 5.72(1H, s), 6.43(1H, d,                                         J=7.7Hz), 7.85(1H, d, J=14.3Hz), 8.52                                         (1H, s)                                    33   C.sub.2 H.sub.5                                                                  H                                                                                ##STR45## H light brown powderly crystal 211-213 (dec)                                         3440, 1720, 1620                                                                     1.09(3H, t, J=7.3Hz), 2.24(3H, s),                                            2.3-2.6(6H, m), 3.1-3.4(5H, m),                                               5.63(1H, s), 5.73(1H, s), 6.87(1H, d,                                         J=7.5Hz), 7.91(1H, d, J=13.4Hz),                                              8.60(1H, s)                                34   C.sub.2 H.sub.5                                                                  H                                                                                ##STR46## H light yellow powderly crystal 164-170 (dec)                                        3425, 1720, 1624                                                                     1.10(3H, t, J=7.3Hz), 2.2-2.7(2H,                                             q-like), 3.0- 3.7(10H, m), 5.64(1H,                                           s), 5.74(1H, s), 6.91(1H, d, J=                                               7.5Hz), 7.96(1H, d, J=13.2Hz),                                                8.62(1H, s)                                35   C.sub.2 H.sub.5                                                                  H                                                                                ##STR47## H light yellow powderly crystal 232-238 (dec)                                        3425, 1730, 1624                                                                     1.10(3H, t, J=7.2Hz), 1.34(3H, d,                                             J=5.3Hz), 2.3- 2.7(3H, m), 2.8-3.8(8H,                                        m), 5.64(1H, s), 5.76(1H, s), 6.91(1H,                                        d, J=7.0Hz), 7.96(1H, d, J=13.0Hz),                                           8.62(1H, s)                                36   C.sub.2 H.sub.5                                                                  H                                                                                ##STR48## H light brown powderly crystal 213-220 (dec)                                         3430, 1715, 1628                                                                     1.09(3H, t, J=7.3Hz), 1.8-2.0(4H, m),                                         2.3-2.7 (2H, q-like), 3.27(1H, s),                                            3.4-3.6(4H, m), 5.58(1H, s), 5.70(1H,                                         s), 6.39(1H, d, J=7.7Hz), 7.77(1H, d,                                         J= 14.5Hz), 8.48(1H,                       __________________________________________________________________________                                       s)                                     

Reference Example 2 Ethyl7-chloro-6-fluoro-1,4-dihydro-1-(1-hydroxyprop-2-yl)-4-oxoquinoline-3-carboxylate

4.11 gm (15.3 mmol) of ethyl7-chloro-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate and 6.32 gm(45.7 mmol) of potassium carbonate anhydride were suspended into 80 mlof N,N-dimethylformamide. To this suspension was added dropwise 20 ml ofa solution of 10.90 gm (45.7 mmol) of1-(tetrahydro-2-pyranyloxy)-2-(methanesulfonyl)propane dissolved inN,N-dimethylformamide with heating at 120° C., and the mixture wasstirred vigorously at 120° C. for 10 hours. The reaction mixture wasfiltered, and the filtrate was concentrated under reduced pressure, and50 ml of acetic acid and 10 ml of water were added to the residue toeffect the hydrolysis at 60° C. for 2 hours. The reaction product wasfiltered and the filtrate was concentrated. The residue was extractedwith chloroform, followed by evaporation of chloroform. The residue thusobtained was purified by silica gel column chromatography(chloroform:methanol=20:1) and recrystallized with a small amount ofchloroform to obtain colorless needlelike crystals of ethyl7-chloro-6-fluoro-1,4-dihydro-1-(1-hydroxyprop-2-yl)-4-oxoquinoline-3-carboxylate.

mp: 238°-239° C.

IR (KBr): 3380, 1723, 1612 cm⁻¹.

¹ H-NMR (CDCl₃) δ ppm: 1.36(3H, t, J=7.1Hz), 1.65(3H, d, J=6.8Hz),2.4-2.8 (1H,br), 3.8-4.2(4H, m), 4.6-5.0(1H, m), 7.51(1H, d, J=9.2Hz),7.76(1H, d, J=5.9Hz), 8.57(1H, s).

Reference Example 3 Ethyl7-chloro-1-(1-chloroprop-2-yl)-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate

7-chloro-6-fluoro-1,4-dihydro-1-(1-hydroxyprop-2-yl)-4-oxoquinoline-3-carboxylateobtained in Reference Example 2 was treated in the same manner as inReference Example 1 to produce colorless prismlike crystals of ethyl7-chloro-1-(1-chloroprop-2-yl)-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate:

mp: 151°-153° C.

IR (KBr): 1725, 1612 cm⁻¹.

¹ H-NMR (CDCl₃) δ ppm: 1.42(3H, t, J=7.1Hz), 1.78(3H, d, J=6.8Hz),3.88(2H, d, J=5.7Hz), 4.41(2H, q, J=7.1Hz), 4.8-5.2(1H, q, like),7.64(1H, d, J=5.5Hz), 8.27(1H, d, J=9.0Hz), 8.56(1H, s).

Example 3 Ethyl6-fluoro-7-(4-methyl-1-piperazinyl)-1-(prop-1-en-2-yl)-1,4-dihydro-4-oxoquinoline-3-carboxylate

Ethyl7-chloro-1-(1-chloroprop-2-yl)-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylateobtained in Reference Example 3 was treated in the same manner as inExample 1 to produce light yellow crystals of ethyl6-fluoro-7-(4-methyl-1-piperazinyl)-1-(prop-1-en-2-yl)-1,4-dihydro-4-oxoquinoline-3-carboxylate (Compound No. 37).

The Compound Nos.38-42 in Table 3 were obtained in the same manner as inthis Example.

                                      TABLE 3                                     __________________________________________________________________________     ##STR49##                                                                     No.poundCom-                                                                       R.sub.1                                                                          R.sub.2                                                                          ##STR50##  R.sub.3                                                                         mp (°C.)Property                                                              (KBr)IR cm.sup.-1                                                                   (DMSO-d.sub.6).sup.1 H-NMR              __________________________________________________________________________                                         ppm                                      37   CH.sub.3                                                                         C.sub.2 H.sub.5                                                                   ##STR51## H colourless needlelike crystals 204-207                                               2950, 1682, 1617                                                                    1.41(3H, t, J=7.0Hz), 2.21(3H, s),                                            2.39(3H, s), 2.4- 2.7(4H, m),                                                 3.1-3.4(4H, m), 4.39(2H, q,                                                   J=7.1Hz), 5.40(1H, s), 5.59(1H, s),                                           6.69(1H, d, J=7.0Hz), 8.04 (1H, d,                                            J=13.2Hz), 8.34(1H, s)                   38   CH.sub.3                                                                         C.sub.2 H.sub.5                                                                   ##STR52## H light yellow crystals 180-182 (dec)                                                  3430, 1705, 1615                                                                    1.41(3H, t, J=7.1Hz), 2.22(4H, s),                                            3.0-3.4(8H, m), 4.39(2H, q,                                                   J=7.1Hz), 5.51(2H, d, J=16.7Hz),                                              6.70 (1H, d, J=7.0Hz), 8.04(1H, d,                                            J=13.4Hz), 8.35(1H, s)                   39   CH.sub.3                                                                         C.sub.2 H.sub.5                                                                   ##STR53## H light brown crystals 144-147                                                         3425, 1724, 1615                                                                    1.14(3H, d, J=6.2Hz), 1.41(3H, t,                                             J=7.3Hz), 1.9- 2.2(1H, br), 2.22(3H,                                          s), 2.2-3.2(5H, m), 3.2- 3.6(2H,                                              d-like), 4.38(2H, q, J=7.3Hz),                                                5.42(1H, s), 5.60(1H, s), 6.68(1H,                                            d, J=7.0Hz), 8.03(1H, d, J=13.6 Hz),                                          8.34(1H, s)                              40   C.sub.2 H.sub.5                                                                  C.sub.2 H.sub.5                                                                   ##STR54## H brown crystals 123-125                                                               3420, 1720, 1615                                                                    1.16(3H, t, J=7.4Hz), 1.41(3H, t,                                             J=7.1Hz), 2.37(3H, s), 2.4-2.8(6H,                                            m), 3.1-3.4(4H, m), 4.38(2H, q, J=                                            7.1Hz), 5.46(1H, s), 5.61(1H, s),                                             6.67(1H, d, J=7.0 Hz), 8.03(1H, d,                                            J=13.4Hz), 8.32(1H, s)                   41   C.sub.2 H.sub.5                                                                  C.sub.2 H.sub.5                                                                   ##STR55## H colourless needlelike crystals 148-151                                               3430, 1722, 1620                                                                    1.16(3H, t, J=7.3Hz), 1.40(3H, t,                                             J=7.0Hz), 1.98(1H, br.s), 2.49(2H,                                            q, J=7.3Hz), 2.8-3.3(8H, m), 4.39                                             (2H, q, J=7.0Hz), 5.42(1H, s),                                                5.58(1H, s), 6.65(1H, d, J=7.0Hz),                                            8.04(1H, d, J=13.2Hz), 8.31(1H, s)       42   C.sub.2 H.sub.5                                                                  C.sub.2 H.sub.5                                                                   ##STR56## H brown needlelike crystals 132-134                                                    3425, 1720, 1612                                                                    1.15(3H, d, J=6.2Hz), 1.16(3H, t,                                             J=7.3Hz), 1.41(3H, t, J=7.0Hz),                                               1.9-2.2(1H, br.s), 2.2-2.6(3H, q-                                             like), 2.6-3.2(4H, m), 3.3-3.6(2H,                                            m), 4.38(2H, q, J=7.0Hz), 5.43(1H,                                            s), 5.59(1H, s), 6.65(1H, d, J=                                               7.0Hz), 8.04(1H, d, J=13.2Hz),                                                8.31(1H, s)                              __________________________________________________________________________

Example 4 6-Fluoro-7-(4-methyl-)-1-piperazinyl)-1-(prop-1-en-2-yl)-1,4-dihydro-4-oxoquinoline-3-carboxylicacid

28 mg (0.078 mmol) of ethyl6-fluoro-7-(4-methyl-1-piperazinyl)-1-(prop-1-en-2-yl)-1,4-dihydro-4-oxoquinoline-3-carboxylate(Compound No. 37) obtained in Example 3 was dissolved in 6 ml of aqueousethanol (ethanol:water=5:1). 0.12 ml of 2N sodium hydroxide was addeddropwise to the solution, followed by hydrolysis with heating underrefluxing for 3 hours. The reaction product was neutralized with 0.2 mlof 1N hydrochloric acid, the mixture was concentrated under reducedpressure, and the residue was extracted with methanol. 24 mg of lightyellow-brown crystals of6-fluoro-7-(4-methyl-1-piperazinyl)-1-(prop-1-en-2-yl)-1,4-dihydro-4-oxoquinoline-3-carboxylicacid (Compound No. 29) was obtained by evaporating methanol.

Reference Example 4 Ethyl1-(1-chloroprop-2-yl)-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylat

4.45 gm (14.3 mmol) of ethyl6,7-difluoro-1,4-dihydro-1-(1-hydroxyprop-2-yl)-4-oxoquinoline-3-carboxylateand 5.10 gm (42.9 mmol) of thionyl chloride were dissolved into 130 mlof chloroform for reaction with heating under refluxing for 1 hour.After cooling, the solvent was evaporated under reduced pressure, theresidue was purified by silica gel column chromatography(chloroform:methanol=100:1), and recrystallized from ethanol to obtain3.53 gm of colorless, needlelike crystals of ethyl1-(1-chloroprop-2-yl)-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate:

mp: 184°-158° C.

IR (KBr): 1725, 1618, 1598, 1502 cm⁻¹.

¹ H-NMR (CDCl₃) δ ppm: 1.42(3H, t, J=7.1Hz), 1.77(3H, d, J=6.8Hz),3.86(2H, d, J=5.7Hz), 4.41(2H, q, J=7.1Hz), 4.6-5.1(1H, m), 7.37(1H, d,d, J=11.6Hz, 6.1Hz), 8.34(1H, d, d, J=10.3Hz, 9.0Hz), 8.56 (1H, s).

Reference Example 5 Ethyl(3S)-7-(3-aminopyrrolidinyl)-1-(1-chloroprop-2-yl)-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate

660 mg (2 mmol) of ethyl1-(1-chloroprop-2-yl)-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylateand 414 mg (4.8 mmol) of 3S-(-)-3-aminopyrrolidine were dissolved in 40ml of acetonitrile and the mixture was heated under refluxing for 4hours. After the reaction, the solvent was evaporated under reducedpressure and the residue was purified by silica gel columnchromatography (chloroform: methanol:aqueous ammonia=300:6:1) to obtain465 mg of light yellow crystal of ethyl(3S)-7-(3-aminopyrrolidinyl)-1-(1-chloroprop-2-yl)-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate.

mp. 149°-152° C.

IR (KBr): 3415, 1712, 1625, 1512 cm⁻¹.

¹ H-NMR (CDCl₃) δ ppm:

1.39(3H, t, J=7.0Hz), 1.70(2H, s, disappeared by D₂ O), 1.74(3H, d,J=7.0Hz), 3.1-3.9(7H, m), 4.37(2H, q, J=7.0Hz), 8.42(1H, s).

Example 5(3S)-7-(3-aminopyrrolidinyl)-6-fluoro-1,4-dihydro-4-oxo-1-(prop-1-en-2-yl)-quinoline-3-carboxylicacid

753 mg (1.9 mmol) of ethyl(3S)-7-(3-aminopyrrolidinyl)-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylateobtained in Reference Example 5 was dissolved in 50 ml of ethanol, andto this was added 320 mg (5.7 mmol) of pulverized potassium hydroxidefor the reaction with heating under refluxing for 26 hours. Aftercooling, the reaction product was neutralized with 1 N hydrochloric acidto adjust to pH 7-8. The precipitate produced was filtrated, washed withwater, air-dried, and dried under reduced pressure to obtain 597 mg of(3S)-7-(3-aminopyrrolidinyl)-6-fluoro-1,4-dihydro-4-oxo-1-(prop-1-en-2-yl)-quinoline-3-carboxylic acid (Compound No. 43).

mp: 249°-255° C.

IR (KBr): 3375, 1720, 1625, 1502 cm⁻¹.

¹ H-NMR (d₆ -DMSO) δ ppm: 1.6-2.2(2H, m), 2.23(3H, s), 3.0-4.4(3H,br),3.2-3.8(5H, m) 5.51(1H, s), 5.71(1H, s), 6.43(1H, d, J=7.7Hz),7.79(1H, d J=14.3Hz), 8.51(1H, s).

TEST EXAMPLE 1 Antimicrobial Activity

Antimicrobial activities agent bacteria listed in Table 4 were measuredaccording to the MIC measurement method of The Japan ChemotherapeuticAssociation. Ofloxacin was used as a control. The results are shown inTable 4.

Medium: Mueller Hinton Medium

Sample dilution: A 1000 mcg/ml solution in 25% dimethyl sulfoxide wasprepared. A series of solutions with various concentrations (100mcg-0.006 mcg) were prepared by successively diluting the solution withsterilized water by a factor of 1/2.

Amount of inoculated bacteria: 10⁶ /ml.

Cultivation conditions: 37° C., 48 hours.

Determination: After 24 hours.

                  TABLE 4                                                         ______________________________________                                                         TEST COMPOUNDS (MIC                                                           degree: mg/ml)                                               STRAINS FOR THE TEST                                                                             Compound No. 43                                                                            Ofloxacin                                     ______________________________________                                            Gram Positive Bacteria                                                    1.  Bacillus subtilis ATCC 6633                                                                      0.049        0.098                                     2.  Staphylococcus aureus FDA                                                                        0.049        0.098                                         209P                                                                      3.  Staphylococcus aureus                                                                            0.39         0.78                                          Terashima                                                                 4.  Staphylococcus aureus Smith                                                                      0.049        0.195                                     5.  Staphylococcus epidermidis                                                                       0.39         0.78                                          ATCC 12228                                                                6.  Sarcina lutea ATCC 9341                                                                          0.78         3.12                                      7.  Streptococcus faecalis IFO                                                                       0.78         1.56                                          12964                                                                     8.  Micrococcus lysodeikticus IFO                                                                    0.39         1.56                                          3333                                                                          Gram Negative Bacteria                                                    9.  Escherichia coli 0-1                                                                             0.098        0.098                                     10. Escherichia coli K-12                                                                            0.098        0.098                                     11. Pseudomonas aeruginosa IFO                                                                       0.78         0.78                                          13736                                                                     12. Pseudomonas aeruginosa P.sub.2                                                                   0.78         0.78                                      13. Pseudomonas aeruginosa IFO                                                                       3.12         3.12                                          12582                                                                     14. Klebsiella pneumoniae ATCC                                                                       0.012        0.012                                         10031                                                                     15. Proteus vulgaris OXK                                                                             0.024        0.024                                     16. Serratia marcescens NHL                                                                          0.098        0.049                                         Methicillin Resistant                                                         Staphylococcus                                                            17. M.R. Staphylococcus aureus                                                                       0.195        0.39                                          395                                                                       18. M.R. Staphylococcus aureus                                                                       0.195        0.39                                          415                                                                       19. M.R. Staphylococcus aureus                                                                       0.098        0.195                                         419                                                                       20. M.R. Staphylococcus aureus                                                                       0.098        0.195                                         420                                                                       21. M.R. Staphylococcus aureus                                                                       0.098        0.195                                         421                                                                       ______________________________________                                    

Table 4 shows that the compounds of this invention have strongerantimicrobial activity than ofloxacin, and that it is effective as anantimicrobial agent.

Industrial Applicability

The compound (I) of this invention exhibits an excellent antimicrobialactivity and superior absorptivity, and efficiently utilized by livingbodies, so that an antimicrobial agent comprising the same as aneffective component is useful for prevention and cure of infection ofmammal including human being.

What is claimed is:
 1. A quinolone carboxylic acid compound of theformula (I), or a salt thereof ##STR57##
 2. A quinolone carboxylic acidcompound of claim 1, wherein said compound is(3S)-7-(3-aminopyrrolidinyl)-6-fluoro-1,4-dihydro-4-oxo-1-(prop-1-en-2-yl)-quinoline-3-carboxylicacid, or a salt thereof.
 3. An antimicrobial composition comprising aninert carrier and an antimicrobially effective amount of a compoundaccording to claim
 1. 4. An antimicrobial composition comprising aninert carrier and an antimicrobially effective amount of a compoundaccording to claim 2.